Plasma Levels of Plasminogen Activator Inhibitor Type 1 and Vitronectin in Children With Cancer.

BACKGROUND: The plasminogen activator system controls intravascular fibrin deposition; besides, it also participates in a wide variety of physiologic and pathologic processes, including cancer. PROCEDURE: In this study, we examined the levels of plasminogen activator inhibitor 1 (PAI-1) and vitronectin in 32 newly diagnosed pediatric patients with malignancies, determined by enzyme-linked immunosorbent assay between January 2009 and January 2010 and compared them to 35 age-matched healthy children, using SPSS 16.0 software. RESULTS: The mean level of PAI-1 was 23.02 ± 15 (8.2-71.19) ng/mL and vitronectin was 83.10% ± 23.77% (12%-126%) in the tumor group. Thirty-five healthy children in the same age range were enrolled in the control group. The levels of PAI-1 and vitronectin were 23.63 ± 10.44 (11.67-58.85) ng/mL and 85% ± 20.85% (39%-126%), respectively. No significant difference was found between the 2 groups by independent sample t-test (P = .86 and P = .69). CONCLUSIONS: This is a preliminary study done in children with malignancies, investigating PAI-1 and vitronectin. Further study is needed, including larger trials and tumor tissue with histopathological examination as in adults.

The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients.

In this study, blood samples were taken from 200 patients with childhood acute leukaemias, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), and from 100 healthy volunteers (controls). The frequency of the human leucocyte antigen (HLA)-DRB1*04 allele was significantly higher, and the frequencies of the HLA-A23 and HLA-B7 antigens were significantly lower, in patients with ALL compared with controls. Among patients with AML, the frequency of the HLA-B49 antigen and the HLA-DRB1*15 allele were significantly higher, whereas the frequencies of the HLA-A11 and HLA-B38 antigens were significantly lower compared with controls. The frequency of the HLA-DRB1*04 allele was also significantly higher in male patients with ALL and AML, whereas the HLA-DRB1*13 allele was found significantly less frequently in male AML and female ALL patients than in controls. To date, this is the only study to evaluate the associations between HLA molecules and leukaemia in a Turkish population with acute childhood leukaemia.

FISH detection of chimerism in pediatric hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established curative therapy for various malignant and non-malignant diseases. Successful outcome after allogeneic HSCT has been associated with donor chimerism (DC). However, the detection of residual host cells or mixed hemopoietic chimerism (MC) has indicated that donor chimerism is not obligatory following HSCT. More recently, fluorescence in situ hybridization (FISH) analysis has been applied to engraftment studies for the identification of polymorphic or sex chromosomes. In this study, chimerism status was evaluated in 48 sex-mismatched HSCT pediatric patients (17 women/31 men, mean age: 9.02 +/- 3.95 years, range: 2-19) by FISH and the effect of DC or MC on outcome and long-term disease-free survival was documented. The stem cell source was bone marrow in all cases. All of the donors were human leucocyte antigen-identical siblings. FISH was performed on 156 specimens between days +13 and +1878. Donor chimerism was found in 47.9% (23/48) and MC was found in 52.1% (25/48) of the patients. Fifteen of 48 (31.25%) patients died, of whom 12 (80%) were MC and three patients (20%) were DC. The difference in chimerism status (MC or DC) was statistically significant between those patients who died and those still alive (chi(2) = 6.813; P = 0.009).

Secondary hemophagocytic lymphohistiocytosis induced by malaria infection in a child with Langerhans cell histiocytosis.

Since the first description of infection-associated hemophagocytosis (IAHS), the list of precipitating infectious agents causing hemophagocytic syndrome has grown. A lymphohistiocytic proliferation with hemophagocytosis may develop as a result of macrophage activation, viral or bacterial infection, parasitic infestations, or malignancy. The authors report on a 3-year-old boy with Langerhans cell histiocytosis (LCH), who developed IAHS during malaria infection. Hemophagocytic syndromes may complicate the course of LCH and cause diagnostics problems. Malaria is one of many infections that can precipitate secondary hemophagocytic lymphohistiocytosis.

Gender- and age-related distinctions for the in vivo prooxidant state in Fanconi anaemia patients.

Some selected oxidative stress parameters were measured in 56 Fanconi anaemia (FA) patients (42 untransplanted and 14 transplanted), 54 FA heterozygotes (parents) and 173 controls. Untransplanted FA patients showed a highly significant increase in leukocyte 8-hydroxy-2'-deoxyguanosine (8-OHdG) (P = 0.00003) and a borderline increase (P = 0.076) in urinary levels of 8-OHdG versus child controls. These increases were more pronounced in female FA patients (P = 0.00005 for leukocyte 8-OHdG and P = 0.021 for urinary 8-OHdG). Female FA patients also displayed a highly significant excess of spontaneous chromosomal breaks versus male patients (P = 0.00026), in the same female:male ratio ( approximately 1.4) as detected for both leukocyte and urine 8-OHdG levels. Plasma methylglyoxal (MGlx) levels were increased in untransplanted FA patients versus child controls (P = 0.032). The increases in leukocyte and urinary 8-OHdG and in MGlx levels were detected in young FA patients (< or =15 years), whereas patients aged 16-29 years failed to display any differences versus controls in the same age group. A significant increase in oxidized:reduced glutathione (GSSG:GSH) ratio was observed (P = 0.046) in the FA patients aged < or =15 years, whereas those aged 16-29 years, both untransplanted and transplanted, displayed a decrease (P = 0.06) in the GSSG:GSH ratio versus the controls of the respective age groups. No significant changes were detected in plasma levels of vitamin C, vitamin E or uric acid. Transplanted FA patients showed lesser alterations in leukocyte 8-OHdG and in GSSG:GSH ratio versus untransplanted patients. The parents of FA patients displayed a significant increase in plasma MGlx levels (P = 0.0014) versus adult controls. The results suggest a gender- and age-related modulation of oxidative stress in FA patients. The observed increase in urinary 8-OHdG in untransplanted FA patients suggests a proficient removal of oxidized DNA bases.

The effect of bone marrow transplantation on systemic and oral health in Fanconi's aplastic anemia.

Fanconi's anemia (FA) is an autosomal-recessive disorder characterized by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Sixteen children with FA, aged between 4 to 16 were divided into two groups according to treatments. Nine children had bone marrow transplantation and seven children were treated with steroid and/or anapolan. The changes in dental caries, caries-associated microflora, salivary status and periodontal health were investigated in children with FA. Data were analyzed by one-way ANOVA. A statistically significant difference was found in hematological findings between children who have received bone marrow transplantation (BMT+) and the others, who have not received (BMT-). There was no significant difference in dental caries experience, salivary flow rate, buffering capacity, mutans streptococci and Lactobacilli levels between the study groups. A statistically significant difference was found in gingival index, plaque index, bleeding on probing, probing depth scores between the patients with FA in BMT(+) and BMT(-) groups (p<.05). In conclusion, besides systemic control, additional preventive measures during their whole life to maintain oral health is necessary in these children.

Cost-effectiveness of cefepime + netilmicin or ceftazidime + amikacin or meropenem monotherapy in febrile neutropenic children with malignancy in Turkey.

Infection remains the major cause of morbidity and mortality in immunocompromised children with malignancy. In addition, the economic impact of antibiotic treatment should always be evaluated, especially in developing countries. In our center between January 1998 and January 1999, 73 children with hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML)]; 9 children with solid tumors (rhabdomyosarcoma, neuroblastoma) had 87 febrile neutropenic episodes (related to chemotherapy). These children were randomized prospectively into three treatment groups. The first group (n: 28) received cefepime plus netilmicin, while the second group (n: 29) was treated with ceftazidime plus amikacin and the third (n: 30) with meropenem as monotherapy. The aim of the study was to compare the success rates and cost of fourth generation cephalosporin plus aminoglycoside and monotherapy of meropenem with ceftazidime plus amikacin, which is the standard therapy for febrile neutropenia. Microbiologically documented infections were 29.9%, clinically documented infections were 9.2% and 60.9% of the febrile neutropenic episodes were considered to be FUO. Gram-positive microorganisms were the most commonly isolated agents from blood cultures [MRSA (Methicillin Resistant Staphylococcus aureus) in 6 patients and MSSA (Methicillin Sensitive Staphylococcus aureus) in 4 patients]. The success rates were 78.5%, 79.3% and 73.3 % for the 1st, 2nd and 3rd groups respectively. In 4 patients (4.5%) fever responded only to amphotericin-B therapy. There was no statistically significant difference between the three treatment regimens with respect to efficacy, safety and tolerance (chi2 test, p>0.05), but while the third and fourth generation cephalosporins + aminoglycosides were comparable for cost, the monotherapy regimen was the most expensive. The main determining factors for the choice of treatment of febrile neutropenic children, especially in a developing country, are cost, presence of indwelling catheter and the bacterial flora of the unit, as well as efficacy.

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia.

The prognosis of relapsed acute leukemia or chronic leukemia in acute blast crisis is poor and new chemotherapeutic regimens could be useful for these patients. Six relapsed acute lymphoblastic leukemia (ALL), nine relapsed acute myeloblastic leukemia (AML), one chronic myelomonocytic leukemia (CMML) and one chronic myeloid leukemia (CML) in acute blast crisis between three to 18 years (median 10 years) received fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) chemotherapy (CT). Five of the AML relapses were after bone marrow transplantation (BMT) and four were recurrent relapses. At the end of the second course only three patients (2 AML, 1 ALL) were in complete remission (CR). Of the three patients in CR, one patient with AML had her first donor lymphocyte transfusion (DLT) on the 7th day of the second FLAG-IDA course and she is disease-free on the 30th month of the second remission. The remaining two patients were transplanted from unrelated donors in a BMT center abroad on the 5th and 8th month of the last remission and both died with BMT-related complications. Out of 25 courses, seven resulted in fatal infections. The regimen was ineffective in B-cell ALL as in acute blastic crisis of CMML and CML. We could not evaluate the remission-inducing effect accurately in most of the patients due to induction failure. FLAG-IDA appears to be a myelotoxic therapy for relapsed or poor risk leukemia in a developing country. It is not cost-effective; dose modifications or a regimen without IDA may be tried if there is an available marrow donor.

Is AML1/ETO gene expression a good prognostic factor in pediatric acute myeloblastic leukemia?

To assess the clinical significance of AML1/ETO gene detected by nested reverse transcriptase polymerase chain reaction, the outcome of 7 patients with acute myeloblastic leukemia between 3 and 14 years of age were presented. All patients had complete remission (CR) at the end of induction (AML-MRC 10 protocol) and 4 underwent unpurged autologous, 2 allogeneic (from matched siblings) non-T-cell-depleted bone marrow transplantations (BMT) in first CR. One patient died due to allogeneic BMT-related complications, and 4 patients relapsed at 13, 17, 18, and 26 months. Only one patient achieved second CR. All relapsed patients died between 18 and 36 months with resistant disease (n = 3) or infection during salvage chemotherapy (n = 1). Two patients who had autologous BMT are alive and disease free at 44 and 50 months. Although statistical significance could not be shown, event-free survival and overall survival rates of AML1/ETO-positive patients (28.57 and 28.57%, respectively) at 3.5 years were even lower than those of AML1/ETO-negative patients. The results confirm some previous reports that AML1/ETO gene in children and adolescents is not a favorable prognostic factor.

Results of rhabdomyosarcoma treatment in a developing country.

Fifty-one children (median age: 4.5 years; 4 months-16 years) diagnosed with rhabdomyosarcoma were treated in our center between 1980-1999. The primary sites were head and neck in 31.4%, the genito-urinary system in 21.6%, and extremities in 9.8% of the patients. The histopathologic subtypes were embryonal in 80.4%, alveolar in 9.8%, and undifferentiated in 9.8%. The majority of the patients were considered group III (47%) and group IV (25.5%) according the criteria of the Intergroup Rhabdomyosarcoma Study (IRS). Primary total tumour resection was performed in only 27.5% of the patients. The patients were treated with assigned regimens of IRS II and IRS III protocols. Radiotherapy was applied to 92.1% of the patients. Thirty-four patients (66.7%) were lost to follow up, and of the remaining 17 patients, 7 patients (41.2%) died, relapse occurred in 9 patients (52.9%) and 10 patients (58.8%) are alive. The percentage of cases lost to follow up during the first 10 years and the following 9 years of the study were 77.4% and 50%, respectively. In compliance with cancer treatment remains a major problem in developing countries.

National survey of hemapheresis practice in Turkey (1998).

The Turkish Apheresis Group has maintained a national registry for apheresis activities since 1997. The hemapheresis practice of Turkey in 1998 is summarized in brief detail in this article. A total of 30, 136 apheresis procedures were performed at 31 different apheresis centers. At 10 centers, 145 peripheral blood stem cell (PBSC) apheresis were performed on 82 patients in allogeneic setting and at 17 centers, 981 PBSC apheresis were performed on 271 patients in autologous setting. Frequently observed adverse effects during PBSC apheresis were mild tremor and chills, paresthesia and nausea in 15% of the patients and donors. Vascular access complications, particularly observed in autologous setting due to central venous catheters were encountered in 10% of the procedures. Eight hundred and sixty-nine therapeutic plasma exchange procedures were performed at 21 centers on 172 patients, most commonly for neurological disorders and thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Therapeutic cytapheresis procedures like leukapheresis, plateletapheresis and erythrocyte apheresis were performed especially for cytoreduction in myeloproliferative disorders. A total of 204 cytapheresis procedures (66% leukapheresis, 33% plateletapheresis and 1% erythrocytapheresis) were performed on 134 patients in 15 centers. Donor plateletapheresis was the most used apheresis procedure, reaching a total of 28.016 in 1998. Many university hospitals and a few state hospitals are performing above-mentioned apheresis procedures with great success and acceptable side effects. According to these data we are planning prospective trials and will establish National Standards of Practice.

Could Parvovirus B19 Induce a Rejection After Bone Marrow Transplantation in a Patient with Diamond-Blackfan Anemia?

A four year-old-girl with Diamond-Blackfan anemia (DBA) that was resistant to corticosteroid treatment and transfusion dependent underwent (bone marrow transplantation) BMT from HLA identical sibling. The patient was conditioned with busulfan and cyclophosphamide and achieved complete marrow engraftment and mixed chimerism in DNA analysis. For the following 13 months she was not transfusion dependent and had a 100% Karnofsky score. But on the 14th month she had anemia ollowing fever, rash and enteritis. Parvovirus B19 IgM seropositivity confirmed Parvovirus infection. Although intravenous immunoglobulin was administered, bone marrow morphology and DNA analysis revealed rejection. Although mixed chimerism detected shortly after the BMT procedure might raise the possibility of an ongoing slow graft rejection during the relatively stable remission period, we think that parvovirus B19 had also contributed rejection.

Prognostic significance of wilms tumor 1 gene in childhood acute Lymphoblastic Leukemia.

Wilms tumor 1 (WT1) gene is a tumor supressor gene, expressed in malignant and normal hematopoietic progenitor cells. Prognostic significance of this gene in childhood acute lymphoid leukemia (ALL) is not clear. We evaluated the presence of WT1 expression in bone marrow samples of 28 children with de novo ALL at diagnosis by two step RT-PCR. Expression of WT1 gene was detected in 78.5% of patients. There was no correlation between WT1 gene expression and age, sex, FAB type, leukocyte count, and presence of t(4;11) and t(9;22). All patients were treated with modified BFM 86 protocol. There was no difference in the complete remission (CR) rate between WT1 positive and negative patients. Event free survival (EFS) and overall survival (OS) of WT1 positive and negative patients were also not significant. We conclude that expression of WT1 gene is not associated with specific characteristics of ALL blast cells and is not a prognostic factor for CR, remission duration and overall survival.

Detection of BCR/ABL transcripts by reverse transcriptase polimerase chain reaction in pediatric acute Lymphoblastic Leukemia: incidence and clinical eatures.

BCR/ABL expression, which is the molecular equivalent of the Philadelphia chromosome, is an independent poor risk factor in acute lymphoblastic leukemia (ALL). We used a two-step (nested) reverse transcriptase polimerase chain reaction (RT-PCR) assay to examine BCR/ABL expression in the diagnostic bone marrow specimen of children with ALL, prospectively. Among 75 de novo ALL patients, 4 (%5.3) were found to be BCR/ABL- ositive, whereas 4 of 17 relapsed patients (23.5%) were positive. This preliminary study in Turkish children showed an incidence similar to reports from Europe and the U.S.A. More intensive chemotherapies and allogeneic bone marrow transplantations (BMT) uring the first remission were planned if a donor was available. Out of 8 BCR/ABL-positive patients, complete remission (CR) was achieved in 7 patients and partial remission (PR) was achieved in 1 patient. Three patients underwent allogeneic BMT during the first CR and 1 under went autologous BMT during the first PR. The Kaplan-Meier estimate of vent-free survival (EFS) of BCR/ABL negative de novo ALL patients was 78.36% at 3 years, whereas the EFS of positive patients was 31.25% at 26 ± 6.4 months. Molecular screening for the Philadelphia chromosome should become a part of the routine diagnostic panel in ALL patients in order to predict which patients have a poor prognosis and need tailored therapy.

Acute lymphoblastic leukemia: dental health of children in maintenance therapy.

The dental health of 41 children aged 4-16 years who were in maintenance therapy from acute lymphoblastic leukemia (ALL) was examined in relation to the period of time in maintenance. There was no significant difference in dental experience and salivary flow rate between the control group and patients with leukemia. Performed treatment index (PTI) and required treatment index (RTI) scores reflected that children, who were in maintenance therapy had insufficient dental care and needed more dental treatments. A statistically significant difference in salivary pH was found between the children, who were in maintenance therapy for 12-24 months and less than 12 months and also the control group; but the pH scores of all groups were observed in normal limits.